Fellowship for Jang: Shoc2 mediates hematopoietic signals of the ERK1/2 pathway

The aberrant ERK1/2 signaling is one of the leading causes of cardiovascular disorders, blood defects and frequent congenital abnormalities that are cumulatively called RASopathies. Therefore, controlling the ERK1/2 activity through the Ras-RAF-MEK-ERK pathway has been a long-time key pharmaceutical objective in cardiac research. ERK1/2 signaling is controlled by scaffold proteins that assemble unique multi-protein signaling complexes and determine specific biological outputs of the pathway by defining ERK1/2 substrates. This project is focused on the scaffold protein Shoc2, a Ras-RAF1- binding protein that accelerates ERK1/2 activity. The objective of this proposal is to determine the mechanisms that control Shoc2-mediated ERK1/2 signals and define the role of Shoc2 in hematopoiesis. We have shown that Shoc2 integrates ubiquitin machinery VCP to regulate ERK1/2 signaling. We also found that the depletion of Shoc2 in zebrafish results in defects in hematopoiesis. Based on this preliminary data, we hypothesize that Shoc2 integrates the ubiquitin machinery to regulate ERK1/2 signals for hematopoiesis. Our hypothesis will be tested by pursuing two specific aims: Aim 1 will define the molecular mechanisms by which VCP controls Shoc2 function, and Aim 2 will delineate the hematopoietic Shoc2-mediated ERK1/2 signals in vivo. The proposed Aims together are expected to provide new insights into the molecular mechanisms that control Shoc2-mediated ERK1/2 signals and define the role of Shoc2 in hematopoiesis. This research has significance for providing valuable insights into normal human development and pathogenesis of congenital disease. This study will also provide critical insights into the circumstances under which cardiovascular pathogenesis is likely to occur, and the role scaffolds play in this process. Knowing that ERK1/2 signals are involved in regulation of hematopoiesis, this study will also lead to a novel understanding of the circumstances under which the deregulation of the ERK1/2 pathway is involved in blood-related pathologies.